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Hand-foot-and-mouth disease 

Updated 2013 Jun 13 12:18:00 PM: inactivated alum-adjuvant enterovirus 71 vaccine decreases risk of EV71-associated hand, foot, and mouth disease in infants and young children in China (Lancet 2013 Jun 8) view updateShow more updates

Related Summaries: 

Herpangina

General Information Description: 

highly contagious viral infection primarily affecting infants and children, characterized by(1, 2, 3) o fever o painful oral lesions o rash on hands and feet

Also called: 

HFMD

Organs involved:  

oral cavity including hard palate, tongue, and buccal mucosa (1, 2, 3) skin(1, 2, 3) o sides of fingers and dorsal surfaces o palms of hands o soles of feet o knees, elbows, buttocks, and/or genital area (less common) nail matrix(1, 2)

Who is most affected:   

usually occurs in infants and children < 10 years old(1, 3) occurs less often in adults(1) in temperate climates, peak incidence occurs in spring, late summer, and early fall(1, 3)

Incidence/Prevalence:


 

hand-foot-and-mouth disease occurs worldwide, both sporadically and in epidemics(2, 3) epidemics occur about once every 3 years in United States(2, 3) o 63 cases of severe hand-foot-and-mouth disease mostly associated with Coxsackie virus A6 (rare cause in United States) reported in 4 states between November 2011 and February 2012 (MMWR Morb Mortal Wkly Rep 2012 Mar 30;61:213 ) enterovirus 71-associated outbreaks most common in East and Southeast Asia (1) o 78 cases of hand-foot-and-mouth disease (including 54 deaths) associated with enterovirus 71 reported in Cambodia in 2012 (WHO Disease Outbreak News 2012 Jul 13) o review of widespread outbreak in Shanghai, China in 2009-2010 involving 3,208 patients can be found in Scand J Infect Dis 2012 Apr;44(4):297 o 2008 outbreak in China  4,496 cases of hand-foot-and-mouth disease due to enterovirus 71 in infants and young children reported  22 deaths reported, all in Fuyang City, Anhui Province, China  Reference - WHO Disease Outbreak News 2008 May 7 o 1998 outbreak in Taiwan (largest epidemic)  129,106 cases of hand-foot-and-mouth disease or herpangina reported  78 patients died  91% were < 5 years old  83% had pulmonary edema or pulmonary hemorrhage  Reference - N Engl J Med 1999 Sep 23;341(13):929 , editorial can be found in N Engl J Med 1999 Sep 23;341(13):984, commentary can be found in N Engl J Med 2000 Feb 3;342(5):355

Causes and Risk Factors Causes: 

enteroviruses(1, 2, 3) o usually Coxsackie virus A16 or enterovirus 71 o sporadic cases may occur secondary to  Coxsackie virus A4-7, A9, A10  Coxsackie virus B1-3, and B5

Pathogenesis: 

transmission(1, 2, 3) o virus transmitted by oral-oral or fecal-oral exposure to infected person, surface, or object through contact with  aerosolized droplets of nasal/oral secretions (saliva, sputum, mucus)  fluid from blisters  stool o may be transmissible weeks after symptoms have resolved


o o o

can be transmitted from mother to fetus cannot be transmitted to or from animals Coxsackie virus may survive on dry inanimate surfaces for several days (BMC Infect Dis 2006 Aug 16;6:130 ) following contact with infected person, surface, or object(1, 2, 3) o virus implants in buccal or ileal mucosa and progresses to lymph nodes within 24 hours o incubation period about 3-6 days o 12-36 hour prodrome may develop with fever after incubation period o painful oral lesions may appear after 1-2 days, followed by skin rash o neutralizing serum antibodies usually develop by day 7

Likely risk factors:   

contact with infected person(1) changing diapers or toilet training infected children may increase risk in parents, day care employees, and teachers (CDC 2011 Feb 28) exposure to crowded settings and infrequent hand washing associated with increased risk of hand-foot-and-mouth disease and herpangina in children o based on case-control study o 176 children with hand-foot-and-mouth disease (HFMD) and herpangina matched to 201 asymptomatic children and given parental questionnaire to assess exposures and hygienic behaviors o risk factors for HFMD and herpangina include  playing with neighborhood children (odds ratio [OR] 11, 95% CI 6.2-17)  visiting outpatient clinic for another reason ≤ 1 week before onset (OR 20, 95% CI 5-88)  community exposure to crowded places (OR 7.3, 95% CI 4.1-13) o frequent hand washing associated with lower risk of infection (OR 0.0007, 95% CI 0.0022-0.022) o Reference - Pediatrics 2011 Apr;127(4):e898 kindergarten/child care center attendance, contact with infected person, greater number of siblings, and residence in a rural area associated with increased risk of EV71-associated hand-foot-and-mouth disease and herpangina in preschool-aged children o based on prospective cohort study o 5,158 patients in Taiwan during enterovirus 71 (EV71)-associated HFMD/herpangina epidemic had neutralizing antibodies to EV71 assayed and completed questionnaire for demographic variables, exposure history, and clinical outcomes evaluated  539 patients assessed prior to outbreak  4,619 patients assessed after outbreak o 29% of preschool-aged children (140 of 484 children) with EV71 infections developed HFMD/herpangina o factors associated with EV71 infection in preschool-aged children


o

kindergarten/child care attendance (adjusted odds ratio [OR] 1.8, 95% CI 1.3-2.5)  contact with infected person (adjusted OR 1.6, 95% CI 1.2-2.1)  increased number of children in family (adjusted OR 1.4, 95% CI 1.1-1.7)  living in rural area (adjusted OR 1.4, 95% CI 1.2-1.6)  older age (adjusted OR 2.5, 95% CI 1.9-3.4) Reference - Pediatrics 2002 Jun;109(6):e88

Complications and Associated Conditions Complications:  

most cases resolve without complications(1, 3) complications linked to underlying viral etiology are rare and may include (1, 2, 3) o temporary nail shedding o myocarditis o pulmonary edema or pneumonia  hyperglycemia associated with increased risk for pulmonary edema in cohort study of 154 children with enterovirus71-associated handfoot-and-mouth disease (HFMD) in Taiwan (Lancet 1999 Nov 13;354(9191):1682)  fulminant pulmonary edema reported in 8-year-old girl with enterovirus 71-associated HFMD in case report (Lancet 1998 Aug 1;352(9125):367), commentary can be found in Lancet 1998 Oct 24;352(9137):1391 o neurologic complications (1, 3)  viral or aseptic meningitis (1, 2, 3)  brainstem encephalitis  symptoms of brainstem encephalitis vary by severity of disease  grade I disease may include  myoclonic jerks  tremor  ataxia  grade II disease may include  myoclonus  cranial nerve involvement  grade III disease may include  transient myoclonus with rapid onset of respiratory distress  cyanosis  poor peripheral perfusion  shock  coma  loss of doll's eye reflex  apnea


Reference - N Engl J Med 1999 Sep 23;341(13):936 , editorial can be found in N Engl J Med 1999 Sep 23;341(13):984, commentary can be found in N Engl J Med 2000 Feb 3;342(5):356 fever ≥ 3 days, peak temperature 101.3 degrees F (38.5 degrees C), and history of lethargy associated with cerebrospinal fluid pleocytosis in children with hand-footand-mouth disease  based on prospective cohort study  725 children with HFMD evaluated  suspected central nervous system involvement and cerebrospinal fluid analysis in 185 children  cerebrospinal fluid pleocytosis identified in 102 children  aseptic meningitis in 63 children (62%)  encephalitis in 33 children (32%)  acute flaccid paralysis in 3 children (3%)  encephalitis associated with cardiorespiratory failure in 3 children (3%)  identified risk factors associated with pleocytosis were validated in independent cohort of 730 children  fever ≥ 3 days  peak temperature ≥ 38.5 degrees C (101.3 degrees F)  history of lethargy  Reference - BMC Infect Dis 2009 Jan 19;9(1):3 brainstem encephalitis reported to be most common neurologic complication in children with enterovirus 71associated hand-foot-and-mouth disease or herpangina (level 3 [lacking direct] evidence)  based on case series  41 children (mean age 2.5 years) with enterovirus 71associated infection were evaluated for neurologic complications  HFMD in 28 children (68%)  herpangina in 6 children (15%)  no skin or mucosal lesions in 7 children (17%)  brainstem encephalitis in 37 children  27 with HFMD  5 with herpangina  5 with no skin or mucosal lesions  mortality in 5 children (14%) with brainstem encephalitis, all with grade III disease  Reference - N Engl J Med 1999 Sep 23;341(13):936 , editorial can be found in N Engl J Med 1999 Sep 23;341(13):984, commentary can be found in N Engl J Med 2000 Feb 3;342(5):356


o

peripheral facial paralysis reported in patient with HFMD in case report (Zhongguo Dang Dai Er Ke Za Zhi 2012 Mar;14(3):235 [Chinese]) o paroxysmal supraventricular tachycardia reported in 11-month-old boy with enterovirus 71-associated HFMD in case report (Ann Dermatol 2012 May;24(2):200 PDF) o coinfection with subgenus B adenovirus reported to increase risk for acute flaccid paralysis and mortality in 10 children with enterovirus 71-associated HFMD in case series (Lancet 1999 Sep 18;354(9183):987), commentary can be found in Lancet 2000 Jan 8;355(9198):146 pregnancy complications (3) o intrauterine growth retardation in first trimester (3) o spontaneous abortion in first trimester o congenital enterovirus 71 infection complicated by fetal hepatosplenomegaly, liver calcification, ascites, hydrocephalus, pleural effusion, and stillbirth at 26 weeks gestation in case report (Clin Infect Dis 2000 Aug;31(2):509)

History and Physical History: Chief concern (CC):  

most infected adults are asymptomatic (1) symptoms may be more severe in infants and young children, and include 1 or both of(1, 2, 3) o painful oral lesions usually on hard palate, tongue, and buccal mucosa o skin rash  may be painful or asymptomatic  usually occurs on hands (most common) and feet  can occur on knees, elbows, buttocks, and/or genital area 12-36 hour prodrome may include(1, 2, 3) o low-grade fever o malaise o cough o reduced appetite and/or dehydration (especially in young children) o abdominal pain o sore mouth or throat

History of present illness (HPI): 

painful oral lesions(1, 2, 3) o usually develop 1-2 days after onset of fever and/or prodrome o usually spontaneously resolve in 5-7 days skin rash(1, 2, 3) o usually develops over 1-2 days, shortly after appearance of oral lesions o may be painful or asymptomatic


  

o usually crusts and resolves in 3-10 days without scarring infected patients most contagious in first week of infection (1) infection may be transmissible weeks after symptoms have resolved (1) ask about (1, 3) o headache, stiff neck, or back pain (may signal meningitis) o ask about myoclonus, tremor, and/or ataxia (may signal brainstem encephalitis)(1, 2, 3) o chest pain, shortness of breath (may signal myocarditis)

Physical: General physical: 

may have low-grade fever(1, 2, 3)

Skin: 

skin rash(1, 2, 3) o more common on hands than feet o may be painful or asymptomatic o less common sites include knees, elbows, buttocks, and/or genital area o characterized by 2-3 mm erythematous macules and/or papules o may progress to central, yellow/gray blisters with axis parallel to skin lines

HEENT: 

oral lesions(1, 2, 3) o 2-8 mm erythematous macules and papules develop into small vesicles on erythematous base o vesicles may develop into painful ulcers (usually 5-10 lesions) o lesions may become confluent and tongue may become red and swollen

Lungs: 

assess for rales which might indicate(2, 3) o pneumonia o pulmonary edema

Extremities: 

may have temporary nail shedding and/or nail loss within 4 weeks of infection (1, 2)

Diagnosis Making the diagnosis:


 

diagnosis usually based on characteristic oral lesions and/or skin rash in infant or child < 10 years old(1) laboratory analysis of throat or stool samples usually not needed but may help confirm diagnosis in patients with severe symptoms(1)

Rule out: 

other viral exanthem infections such as(2, 3) o chickenpox o measles o rubella o scarlet fever o fifth disease o roseola infantum o pityriasis rosea review of differential diagnosis of mouth pain can be found in Aust Fam Physician 2008 Nov;37(11):935

Testing overview:  

testing generally not needed for diagnosis(1) laboratory analysis of throat or stool samples may help confirm diagnosis in cases with severe symptoms(1)

2-step real-time reverse transcriptase-polymerase chain reaction assay of cerebrospinal fluid appears highly sensitive for detection of enterovirus (level 2 [mid-level] evidence) o based on diagnostic cohort study o 74 patients with suspected enterovirus-associated meningitis had cerebrospinal fluid (CSF) samples evaluated by 1-step and 2-step real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay on LightCycler instrument o reference standard was conventional RT-PCR assay o 15 samples (20.3%) were positive for enterovirus by reference standard o comparing diagnostic performance of 1-step vs. 2-step RT-PCR assay for detection of enterovirus  sensitivity 73.3% vs. 100%  specificity 98.3% vs. 96.6%  positive predictive value 91.7% vs. 88.2%  negative predictive value 93.5% vs. 100% o Reference - J Clin Virol 2006 Mar;35(3):278

Treatment Treatment overview:


  

oral lesions usually resolve spontaneously in 5-7 days, and skin lesions usually crust and spontaneously resolve without scarring in 3-10 days supportive treatment may alleviate fever, pain, and inflammation low-level laser therapy may reduce duration of painful stomatitis in patients with hand-foot-and-mouth disease (level 2 [mid-level] evidence)

Medications: 

supportive treatment may alleviate symptoms(1, 2, 3) o over-the-counter medications may reduce fever, pain, and inflammation o treatment options to relieve pain from oral lesions  numbing sprays or mouthwashes  viscous lidocaine  diphenhydramine  sucralfate  dyclonine solutions  magnesium hydroxide o IV fluids may be indicated in patients unable to swallow liquids systemic acyclovir reported to resolve skin lesions in 27-year-old immunocompromised man with hand-foot-and-mouth disease and recent chemotherapy in case report (Australas J Dermatol 2003 Aug;44(3):203)

Other management: 

low-level laser therapy may reduce duration of painful stomatitis in patients with hand-foot-and-mouth disease (level 2 [mid-level] evidence) o based on small randomized trial o 20 patients with stomatitis due to hand-foot-and-mouth disease were randomized to low-level laser therapy (LLLT) vs. placebo and evaluated for duration of painful stomatitis o mean duration of painful stomatitis 4 days with LLLT vs. 6.7 days with placebo (p < 0.005) o successful treatment of painful stomatitis in 18 patients (90%) o no adverse events reported o Reference - J Clin Laser Med Surg 2003 Dec;21(6):363

Prognosis 

most cases resolve without long-term complications(1, 2, 3) o oral lesions usually spontaneously resolve in 5-7 days o skin lesions usually crust and spontaneously resolve without scarring in 3-10 days factors affecting severity of infection (2) o infection usually more severe in infants and children o enterovirus 71-associated infection reported to be more severe than Coxsackie virus-associated infection(2)


o

enterovirus 71 associated with higher transmission rates and more severe disease in children than adults  based on prospective cohort study  94 families (433 family members) with ≥ 1 family member with suspected enterovirus 71 (EV71) infection had clinical exams, virologic evaluations, and questionnaire-based interviews with follow-up for 6 months  52% overall virus transmission rate to household contacts  84% transmission rate among household children vs. 37% among household adults (p < 0.001)  comparing illness in children vs. adults  complicated illness (involving central nervous system or cardiopulmonary failure) in 21% vs. 0% (p < 0.001)  at 6-month follow-up, poor outcomes (including mortality, brainstem encephalitis, and cardiopulmonary failure) in 13% vs. 0% (p = 0.001)  asymptomatic illness in 6% vs. 53% (no p value reported)  uncomplicated illness (including hand-foot-and-mouth disease) in 73% vs. 47% (p < 0.001)  factors associated with EV71 infection in children included  male gender (p = 0.003)  age ≤ 6 years (p = 0.001)  kindergarten or school attendance (p = 0.006)  age < 3 years significantly associated with long-term sequelae or death (p = 0.004)  Reference - JAMA 2004 Jan 14;291(2):222 residual cognitive and motor deficits reported to persist > 2 years in about 14% of children with enterovirus 71-associated brainstem encephalitis (level 3 [lacking direct] evidence) o based on case series o 63 children with enterovirus 71 brainstem encephalitis had cognitive and neurologic exams with evaluation of motor coordination, visual-motor skill, and intellectual ability at mean follow-up 2.8 years  49 children had stage II disease, characterized by ≥ 1 of the following symptoms  myoclonus  ataxia  nystagmus  oculomotor palsies  bulbar palsy  7 children had stage IIIa disease characterized by autonomic nervous system dysregulation  7 children had stage IIIb disease characterized by pulmonary edema o at mean follow-up 2.8 years  51 children had no detectable deficits  3 children had died, all had stage IIIB disease  9 children (14%) had residual cognitive and motor deficits


motor deficits (mostly cerebellar dysfunction) in 7 children  5 with stage II disease  2 with stage IIIb disease  cognitive deficits in 3 children with stage II disease o Reference - Pediatrics 2006 Dec;118(6):e1785 recurrence of hand-foot-and-mouth disease at 3 weeks and 7 months after initial infection in 15-year-old boy in case report (Clin Pediatr (Phila) 2006 May;45(4):373)

Prevention and Screening Prevention: 

inactivated alum-adjuvant enterovirus 71 vaccine decreases risk of EV71associated hand, foot, and mouth disease in infants and young children in China (level 1 [likely reliable] evidence) o based on randomized trial o 10,245 healthy children aged 6-35 months in China randomized to inactivated alum-adjuvant enterovirus 71 (EV71) vaccine vs. placebo on days 0 and 28 and followed to 14 months o enterovirus 71-associated hand, foot, and mouth disease (EV71-HFMD) defined as febrile illness with papulovesicular rash on palms and soles with or without vesicles or ulcers in mouth, buttocks, knees or elbows and positive for EV71 isolation or at least 2 consecutive EV71-specific RNA tests o EV71-associated disease was defined as HFMD, herpangina, neurological signs (aseptic meningitis or encephalitis), or other nonspecific illnesses caused by EV71 virus o 10,226 patients (99.8%) were included in modified intention-to-treat analyses o comparing EV71 vaccine vs. placebo  incidence of EV71-HFMD 0.6 vs. 6.7 per 1,000 person-years (vaccine efficacy 90.9%, p = 0.0001)  incidence of EV71-associated disease 1.6 vs. 9 per 1,000 personyears (vaccine efficacy 81.9%, p < 0.0001)  serious adverse events in 1.2% vs. 1.5% (not significant)  any adverse events in 71.2% vs. 70.3% (not significant) o Reference - Lancet 2013 Jun 8;381(9882):2024, editorial can be found in Lancet 2013 Jun 8;381(9882):1968

activities associated with reduced risk of infection include (1) o frequent hand washing, especially after changing diapers and using bathroom o disinfecting surfaces, toys, and other soiled items after washing with soap and water, with chlorine bleach and water mixture (1 tablespoon bleach to 4 cups water)


o

avoiding close contact with infected persons, including hugging, kissing, and sharing utensils and cups frequent hand washing associated with decreased risk of hand-foot-and-mouth disease and herpangina in children (level 2 [mid-level] evidence) o based on case-control study o 176 children with hand-foot-and-mouth disease (HFMD) and herpangina matched to 201 asymptomatic children and administered questionnaire to assess exposures and hygienic behaviors o hand-washing score determined by questions about frequency of hand washing after play, before eating, and by caregiver washing hands before feeding child o compared to poorest hand-washing score, good hand-washing score associated with decreased risk of infection (odds ratio 0.0007, 95% CI 0.0022-0.022) o Reference - Pediatrics 2011 Apr;127(4):e898 no recommended exclusion period from school (UK expert Grade C, Level I/III) o exclusion not required as this is generally a mild illness in childhood o exclusion will not be fully effective due to prolonged excretion of virus in patients with asymptomatic infections o Reference - Pediatr Infect Dis J 2001 Apr;20(4):380, correction can be found in Pediatr Infect Dis J 2001 Jul;20(7):653, commentary can be found in Pediatr Infect Dis J 2001 Dec;20(12):1184

Guidelines and Resources Guidelines: United Kingdom guidelines: 

expert guideline on exclusion policies for control of communicable disease in schools and preschools can be found in Pediatr Infect Dis J 2001 Apr;20(4):380, correction can be found in Pediatr Infect Dis J 2001 Jul;20(7):653, commentary can be found in Pediatr Infect Dis J 2001 Dec;20(12):1184

Asian guidelines: 

expert guideline on diagnosis and treatment of severe cases with enterovirus 71 (EV71) infection can be found in Zhonghua Er Ke Za Zhi 2011 Sep;49(9):675 [Chinese]

Review articles:   

review can be found in Nihon Rinsho 2007 Mar 28;65 Suppl 3:339 [Japanese] review can be found in Aust Fam Physician 2003 Aug;32(8):594 review on the advancement of epidemiology on hand-foot-and-mouth disease can be found in Zhonghua Liu Xing Bing Xue Za Zhi 2009 Sep;30(9):973 [Chinese]


    

review of human enterovirus 71 and hand-foot-and-mouth disease can be found in Epidemiol Infect 2010 Aug;138(8):1071 review of clinical features, diagnosis, and management of enterovirus 71 can be found in Lancet Neurol 2010 Nov;9(11):1097 review of scavenger receptor b2 as a receptor for hand-foot-and-mouth disease can be found in Front Microbiol 2012;3:32 review of the virology and developments toward control of human enterovirus 71 can be found in Crit Rev Microbiol 2011 Nov;37(4):313 review of picornavirus infections can be found in Arch Fam Med 2000 SepOct;9(9):913, editorial can be found in Arch Fam Med 2000 Sep-Oct;9(9):921

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